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Selective calcium sensitivity in immature glioma cancer stem cells.

ABSTRACT: Tumor-initiating cells are a subpopulation in aggressive cancers that exhibit traits shared with stem cells, including the ability to self-renew and differentiate, commonly referred to as stemness. In addition, such cells are resistant to chemo- and radiation therapy posing a therapeutic challenge. To uncover stemness-associated functions in glioma-initiating cells (GICs), transcriptome profiles were compared to neural stem cells (NSCs) and gene ontology analysis identified an enrichment of Ca2+ signaling genes in NSCs and the more stem-like (NSC-proximal) GICs. Functional analysis in a set of different GIC lines regarding sensitivity to disturbed homeostasis using A23187 and Thapsigargin, revealed that NSC-proximal GICs were more sensitive, corroborating the transcriptome data. Furthermore, Ca2+ drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca2+ sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca2+. Conversely, a higher number of and higher expression levels of Ca2+ binding genes that may buffer Ca2+, were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca2+ sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca2+ drug sensitivity. The correlation between high expression of Ca2+ channels (such as GRIA1) and sensitivity to Ca2+ drugs was confirmed in an additional nine novel GIC lines. Calcium drug sensitivity also correlated with expression of the NSC markers nestin (NES) and FABP7 (BLBP, brain lipid-binding protein) in this extended analysis. In summary, NSC-associated NES+/FABP7+/GRIA1+ GICs were selectively sensitive to disturbances in Ca2+ homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells.

SUBMITTER: Wee S

PROVIDER: S-EPMC4274094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lung Cancer (LC), colorectal cancer (CRC) and breast cancer (BC) are the major killers in oncology, accounting for about 40% of cancer deaths. Although progresses have been made in the last few years, unfortunately no patient with metastatic disease can obtain a definitive cure. A recent hypothesis is that cancer is driven by a small subpopulation of cells called "cancer stem cells" (CSCs) or "tumor initiating cells" with an unlimited proliferative potential and the ability to reproduce the original human tumor in experimental animal models. These cells are thought to be responsible for the development of the tumor and represent the only cell population able to sustain tumor growth and progression. Therefore, CSCs represent the elective target for new targeted therapies, endowed with high and selective toxicity towards the tumor but harmless towards normal cells. Current technologies allow us to isolate and expand in vitro the CSCs from tumor specimens, testing their sensitivity to different anticancer drugs in a short period of time. Therefore, there is the potential opportunity to identify LC, CRC and BC CSCs.This is a prospective study assessing feasibility of CSCS isolation in LC, CRC and BC. Patients with a previously performed diagnosis of LC, colon cancer or breast cancer with no further standard therapy options, with a Karnofsky performance status of 100% and with tumor tissue available will be considered eligible for the study. Tumor tissue will be collected before study entry, i.e tissue obtained during a diagnostic or therapeutical procedure, like surgery or biopsies with other purposes than the protocol. In vitro tumor sensitivity to chemotherapy drugs will be tested on tumor cell cultures per each patient. Drugs and their combination will be considered effective and if they kill ≥ 60% of tumor stem cells in vitro test. By using cancer spheres the investigators will also generate orthotopic xenograft models that recapitulate the parental tumor behaviour, including the aggressive features and the invasiveness potential. Orthotopic injection technique will be assessed in 5 weeks-old NOD/SCID mice

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Selective calcium sensitivity in immature glioma cancer stem cells.

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